THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS VOLUME 3 DANIEL LEDNICER Analytical Bio-Chemistry Laboratories, Inc. Columbia, Missouri LESTER A. MITSCHER The University of Kansas School of Pharmacy Department of Medicinal Chemistry Lawrence, Kansas A WILEY-INTERSCIENCE PUBLICATION JOHN WILEY AND SONS New York • Chlchester • Brisbane * Toronto • Singapore Copyright © 1984 by John Wiley & Sons, Inc. All rights reserved. Published simultaneously in Canada. Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc. Library of Congress Cataloging In Publication Data: (Revised for volume 3) Lednicer, Daniel, 1929- The organic chemistry of drug synthesis. "A Wiley-lnterscience publication." Includes bibliographical references and index. 1. Chemistry, Pharmaceutical. 2. Drugs. 3. Chemistry, Organic—Synthesis. I. Mitscher, Lester A., joint author. II. Title. [DNLM 1. Chemistry, Organic. 2. Chemistry, Pharmaceutical. 3. Drugs—Chemical synthesis. QV 744 L473o 1977] RS403.L38 615M9 76-28387 ISBN 0-471-09250-9 (v. 3) Printed in the United States of America 10 907654321 With great pleasure we dedicate this book, too, to our wives, Beryle and Betty. The great tragedy of Science is the slaying of a beautiful hypothesis by an ugly fact. Thomas H. Huxley, "Biogenesis and Abiogenisis" Preface Ihe first volume in this series represented the launching of a trial balloon on the part of the authors. In the first place, wo were not entirely convinced that contemporary medicinal (hemistry could in fact be organized coherently on the basis of organic chemistry. If, however, one granted that this might be done, we were not at all certain that the exercise would engage Ihe interest of others. That book's reception seemed to give nri affirmative answer to each of these questions. The second volume was prepared largely to fill gaps in the coverage and to bring developments in all fields up to a common date - 1976. In the process of preparing those volumes, we formed the habit of scrutenizing the literature for new nonproprietary names as mi indication of new chemical entities in or about to be in the « linic. It soon became apparent that the decreased number of drugs being granted regulatory approval was not matched by a decrease in the number of agents being given new generic Mrtmes, The flow of potential new drugs seemed fairly constant over the years. (For the benefit of the statistician, assign- ment of new USAN names is about 60 per year.) It was thus ix x PREFACE obvious that the subject matter first addressed in Volume 1 was increasing at a fairly constant and impressive rate. Once we had provided the background data up to 1976, it seemed logical to keep the series current by adding discussion of newer agents. Reports of drugs for new indications as well as the occurrence of brand-new structural types as drugs made it particularly important to update the existing volumes. The five-year cycle for preparation of new volumes represents a compromise between timeliness and comprehensiveness. A shorter period would date earlier entries. This volume thus covers compounds reported up to 1982. As has been the practice in the earlier volumes, the only criterion for including a new therapeutic agent is its having been assigned a United States nonproprietary name (USAN), a so-called generic name. Since the focus of this text is chemistry, we have avoided in the main critical comments on pharmacology. The pharmacological activity or therapeutic utility described for the agents covered is that which was claimed when the USAN name was assigned. The changes in chapter titles as well as changes in their relative sizes in going from volume to volume constitute an interesting guide to directions of research in medicinal chemistry. The first two volumes, for example, contained extensive details on steroid drugs. This section has shrunk to about a third of its former size in this book. The section on 3-lactam antibiotics, on the other hand, has undergone steady growth from volume to volume: not only have the number of entries multiplied but the syntheses have become more complex. PREFACE xi This book, like its predecessors, is addressed to students <d the graduate level in organic and medicinal chemistry as well as to practitioners in the field. It is again assumed that the reader has a comfortable grasp of organic synthesis as well as a basic grounding in biology. We are pleased to acknowledge the helpful assistance of '.overal individuals in preparing this volume. Particularly, we «ina grateful to Mrs. Janet Gill for preparing all of the illustrations and to Mrs. Violet Huseby for long hours and (cireful attention to detail in preparing the final copy and several drafts. Daniel Lednicer Dublin, Ohio I «*ster A. Mitscher Lawrence, Kansas January, 1984 Contents Chapter 1. Alicyclic and Cyclic Compounds 1 1. Cyclopentanes 1 a. Prostaglandins 1 b. Retenoids 11 c. Miscellaneous 13 References 16 Chapter 2, Phenethyl and Phenoxypropanolamines 19 1. Phenylethanolamines 20 References 34 Chapter 3. Arylaliphatic Compounds 37 1. Arylacetic Acid Derivatives 37 2. Anilines, Benzyl Amines, and Analogues 45 3. Diarylmethane Analogues 47 4. Stilbene Analogues 50 References 52 Chapter 4. Monocyclic Aromatic Agents 55 1. Aniline Derivatives 55 2. Benzoic Acid Derivatives 58 3. Benzenesulfonic Acid Derivatives 61 References 63 Chapter 5. Polycyclic Aromatic Compounds 65 1, Indanones 65 xi i i XIV CONTENTS 2. Naphthalenes 68 3. Tricyclic Compounds: Anthracene, Phenanthrene, and Dibenzocycloheptene 72 References 78 Chapter 6. Steroids 81 1. Estranes 82 2. Androstanes 87 3. Pregnanes 90 4. Miscellaneous Steroids 99 References 107 Chapter 7. Compounds Related to Morphine 109 1. Bridged Polycyclic Compounds 111 2. Piperidines 116 3. Miscellaneous Compounds 121 References 124 Chapter 8. Fi\ /e-Membered Heterocycles 127 1. Pyrroles and Pyrrolidines 127 2. Furans 129 3. Imidazoles 131 4. Triazoles 137 5. Pyrazolines 137 6. Isoxazoles 138 7. Tetrazoles 139 8. Miscellaneous 139 References 141 Chapter 9. Six-Membered Heterocycles 145 1, Pyri dines 145 2. Pyridazines 151 3. Pyrimidines 152 4. Miscellaneous Heterocycles 157 References 162 Chapter 10. Five-Membered Heterocycles Fused to Benzene 165 1. Indoles 165 2. Benzimidazoles 172 3. Benzothiazoles 178 References 179 Chapter 11. Benzofused Six-Membered Heterocycles 183 1. Quinoline Derivatives 183 2. Isoquinoline Derivatives 186 CONTENTS xv 3. Benzopyran Derivatives 188 4. Benzodioxane Derivatives 191 5. Benzoxazolinone Derivatives 191 6. Quinazolinone Derivatives 192 7. Phthalazines 195 8. Benzodiazapines and Related Substances 195 9. Miscellaneous 198 References 199 Chapter 12. Beta Lactams 203 1. Penicillins 203 2* Cephalosporins 209 References 221 Chapter 13. Miscellaneous Fused Heterocycles 225 References 250 Cross Index of Drugs 253 Cumulative Index, Vols. 1-3 261 Index 279 THE ORGANIC CHEMISTRY OF DRUG SYNTHESIS VOLUME 3 1 Alicyclic and Cyclic Compounds 1. CYCLOPENTANES a. Prostaglandins. Few areas of organic medicinal chemistry in recent memory have had so many closely spaced pulses of intense research activity as the prostaglandins. Following closely on the heels of the discovery of the classical monocyclic prostaglandins (prosta- glandin El9 F2, A2, etc*)* with their powerful associated act- ivities, for example, oxytocic, blood pressure regulating, and inflammatory, was the discovery of the bicyclic analogues (the thromboxanes, prostacyclin) with their profound effects on hemodynamics and platelet function. More recently, the non- cyclic leucotrienes, including the slow releasing substance of anaphylaxis, have been discovered. The activity these sub- stances show in shock and asthma, for example, has excited con- siderable additional interest. Each of these discoveries has opened new physiological and therapeutic possibilites for ex- ploitation. The newer compounds in particular are chemically and biologically short lived and are present in vanishingly small quantities so that much chemical effort has been expended 2 ALICYCLIC AND CYCLIC COMPOUNDS on finding more efficient means of preparing them, on enhancing their stability, and on finding means of achieving greater tis- sue specificity. In addition to its other properties, interest in the potential use of the vasodilative properties of prostaglandin Ei, alprostadil (4^), has led to several conceptually different syntheses.1**5 For this purpose, the classic Corey process1 has to be modified by reversing the order of addition of the side chains to allow for convenient removal of the unwanted double bond in the upper side chain. For example, Corey lactone jL_ is protected with dihydropyran (acid catalysis), reduced to the lactol with diisobutyaluminum hydride, and then subjected to the usual Wittig reaction to give intermediate 2^. This is esterified with diazomethane, acetylated, and then catalytic- ally hydrogenated to give intermediate 3^ in which all of the oxygen atoms are differentiated. Further transformation to al- prostadil (£) follows the well-trodden path of sequential Collins oxidation, Horner-Emmons olefination, zinc borohydride reduction, deetherification with aqueous acetic acid, separ- r 2 .6o 6thp - - . othp (I) (2) (31 0 ,.(CH? Oil Oil (4) ALICYCLIC AND CYCLIC COMPOUNDS 3 ation of the resulting C-15 epimers, dihydropyranylation,